Synthesis, Biological Evaluation, and Utility of Fluorescent Ligands Targeting the μ‑Opioid Receptor

Fluorescently labeled ligands are
useful pharmacological research
tools for studying receptor localization, trafficking, and signaling
processes via fluorescence imaging. They are also employed in fluorescent
binding assays. This study is centered on the design, synthesis, and
pharmacological evaluation of fluorescent probes for the opioid receptors,
for which relatively few non-peptidic fluorescent probes currently
exist. The known μ-opioid receptor (MOR) partial agonist, buprenorphine,
was structurally elaborated to include an amidoalkylamine linker moiety
that was coupled with a range of fluorophores to afford new fluorescent
probes. All compounds proved to be selective MOR antagonists. Confocal
fluorescence microscopy studies revealed that the probe incorporating
a sulfonated cyanine-5 fluorophore was the most appropriate for imaging
studies. This ligand was subsequently employed in an automated fluorescence-based
competition binding assay, allowing the pKi values of several well-known opioid ligands to be determined. Thus,
this new probe will prove useful in future studies of MOR receptor
pharmacology.